Endogenous opiate receptors were discovered in the 1970s, and have been intensely studied in seeking the mechanisms by which particular drugs lead to addiction. However, such mechanisms have remained elusive. See, for example, J. Neurosci., 12(7): 2349-2450 (1992).
A number of different opioid receptor types have been identified. Known receptor types include, for example, the mu xcexc (MOR), delta xcex4 (DOR), and xcexa kappa receptors. Narcotic analgesics act at the opioid xcexc receptor to produce analgesia. The xcexc receptor mediates analgesia, respiratory depression, and inhibition of gastrointestinal transit. As such, narcotic analgesics act at the xcexc receptor to produce analgesia. However, continued use of narcotic analgesics typically leads to habit or addiction, and use of one leads to cross-tolerance/dependence for the others. Despite their therapeutic uses, undesirable side effects such as physical dependence and drug craving can develop.
Opiates, are a class of centrally acting compounds and are frequently used agents for pain control. Opiates are narcotic agonistic analgesics and are drugs derived from opium, such as morphine, codeine, and many synthetic congeners of morphine, with morphine being the most widely used derivative. Opioids are natural; and synthetic drugs with morphine-like actions and include the opiates. Opioids are narcotic agonistic analgesics which produce drug dependence of the morphine type and are subject to control under federal narcotics law because of their addicting properties. The chemical classes of opioids with morphine-like activity are the purified alkaloids of opium consisting of phenanthrenes and benzylisoquinolines, semi-synthetic derivatives of morphine, phenylpiperidine derivatives, morphinan derivatives, benzomorphan derivatives, diphenyl-heptane derivatives, and propionanilide derivatives.
Physical dependence or drug addiction to narcotic drugs, for example, opioids, has been traditionally treated by drug withdrawal through administering an opioid antagonistic drug such as naltrexone or naloxone, withholding the opioid from the drug-dependent individual, gradually decreasing the amount of opioid taken by the individual over time, or substituting another drug, such as methadone, buprenorphine, or methadyl acetate, for the opioid to ameliorate the physical need for the opioid. When an opioid is discontinued, withdrawal symptoms appear, the character and severity of which are dependent upon such factors as the particular opioid being withdrawn, the daily dose of the opioid that is being withdrawn, the duration of use of the opioid, and the health of the drug dependent individual. The pain associated with withdrawal symptoms can be quite severe.
For example, the withdrawal of morphine, heroin, or other opioid agonists with similar durations of action from an individual dependent upon the opioid gives rise to lacrimation, rhinorrhea, yawning, and sweating 8 to 12 hours after the last dose of the opioid. As withdrawal progresses, the individual will be subject to dilated pupils, anorexia, gooseflesh, restlessness, irritability, and tremor. At the peak intensity of withdrawal, which is 48 to 72 hours for morphine and heroin, the individual suffers from increasing irritability, insomnia, marked anorexia, violent yawning, severe sneezing, lacrimation, coryza, weakness, depression, increased blood pressure and heart rate, nausea, vomiting, intestinal spasm, and diarrhea. The individual commonly experiences chills alternating with hot flushes and sweating, as well as abdominal cramps, muscle spasms and kicking movements, and pains in the bones and muscles of the back and extremities, and exhibits leukocytosis and an exaggerated respiratory response to carbon dioxide. Typically the individual does not eat or drink which, when combined with the vomiting, sweating, and diarrhea, results in weight loss, dehydration, and ketosis. The withdrawal symptoms from morphine and heroin usually disappear in 7 to 10 days, but the drug dependent individual suffers greatly during the withdrawal period.
Alternatively, if an opioid antagonistic drug is administered to the individual, such as naloxone or naltrexone, withdrawal symptoms develop within a few minutes after parenteral administration and reach peak intensity within 30 minutes, with a more severe withdrawal than from withholding the opioid. For example, naloxone is the current treatment of choice in cases of overdose. It is immediately effective but is encumbered by intense withdrawal syndrome. Naltrexone can be used, for example, in maintenance therapy, but is quite aversive, which impedes wide acceptance and efficacy. Since addiction to cocaine and alcohol have been reported to also be mediated by specific opioid-sensitive brain cell networks (See, Gardner et al., Substance Abuse 2nd Ed., pp. 70-99 (1992)) the use of opioid antagonists can be suitable for use in the treatment of alcohol and cocaine dependency. Thus, the opioid receptors can play a role in the dependency of multiple drug substances.
The use of opioid analgesics for the treatment of pain and during and/or after anesthesia can also lead to unwanted side effects, for example, respiratory depression. It is frequently necessary to titrate back or adjust the degree of analgesic/anesthesia in an individual receiving opioid pain management, for example, undergoing or recovering from a surgical procedure, due to complications associated with too high of a dose. The use of naltrexone and naloxone present undesirable side effects such as exacerbation respiratory depression when used to titrate back. Further, use of opioid analgesics for chronic pain can often be associated with constipation which can be a significant and limiting problem. There is currently no known treatment strategy to reduce the constipating effects of the opioid analgesics without blocking the analgesic effect and/or causing additional side effects (e.g., diarrhea and hyperalgesia).
Therefore, a need exists for agents which can be used in the treatment of drug dependency or in pain management to, for example, modify the anesthesia/analgesia of an opioid drug or its unwanted side effects but which have reduced aversive properties and can result in reduced withdrawal symptoms.
The invention relates to the use of naltrexone and naloxone analogs, which are neutral antagonists at the xcexc opioid receptor, for the treatment of drug dependency in a drug-dependent individual. Surprisingly, it has been found that administration of a therapeutically effective amount of the naloxone or naltrexone analogs described herein for the treatment of a drug dependency, can result in reduction of undesirable side effects resulting from current treatments using naloxone and naltrexone. For example, the treatment described herein can result in a reduction in the withdrawal symptoms and aversion encountered in the use of naloxone and naltrexone in the treatment of drug dependency. In addition, the naltrexone and naloxone analogs of the invention can be used for modulating the treatment of pain or anesthesia in an individual in need thereof by decreasing or reversing the effects of high doses of the narcotic analgesic, for example, respiratory depression, or decreasing side effects such as constipation without blocking analgesia.
U.S. Pat. No. 6,007,986, teaches that the xcexc opioid receptor has a constitutively active state that may be represented as xcexc*. The xcexc opioid receptor is the main mediator of narcotic analgesia and addiction and can be classified as a G protein coupled receptor (GPCR). This feature of basal level signalling activity is emerging as a recognized feature of a number of GPCRs, for example, the dopamine receptors, D1, D2 and D3, the adenosine receptor, the xcex22-adrenergic receptor, the serotonin receptor (5HT-2A) and the xcex4-opioid receptors. In the naive state (no prior drug exposure), the activity of the xcexc* state is minimal, and most receptors are drug sensitive. Recent findings, indicate that the xcexc opioid receptor differs in its characteristics significantly between drug-naive and drug-tolerant/dependent states, with the constitutive or spontaneous activity of the xcexc opioid receptor being enhanced in the tolerant/dependent state.
In general, compounds which exhibit antagonistic behavior at a particular GPCR having basal signalling activity, for example the xcexc opioid receptor, can be categorized as either neutral antagonists or inverse agonists based on the effect which they exhibit upon the basal signalling activity of the particular receptor for which they are a ligand following interaction. xe2x80x9cNeutral antagonistsxe2x80x9d are agents which block the affects of an agonist at the target receptor but do not significantly effect the level of spontaneous receptor activity. xe2x80x9cInverse agonistsxe2x80x9d are agents which block the effects of an agonist at the target receptor and also suppress spontaneous receptor activity.
Individual opioid drugs fall on a sliding scale of efficacy from full agonist to full inverse agonists. It appears possible that these pharmacological properties of a drug can change, however, during long-term stimulation. For example, it has been determined that the prototypical opioid antagonists naloxone and naltrexone, which display neutral antagonistic behavior at an untreated xcexc opioid receptor, behave as inverse agonist at drug-pretreated, for example, morphine pre-treated receptors. This switch in pharmacological effects at untreated or drug-pretreated receptors can be at least in part responsible for the severe withdrawal symptoms experienced by drug-dependent individual upon administration of naloxone and naltrexone. Thus, withdrawal symptoms can be a result of not only the blocking of agonist effects, but the inverse agonist effect of naloxone and naltrexone on the spontaneously active xcexc opioid receptor.
Neutral antagonists against receptors exhibiting spontaneous activity can be determined with the use of in vitro assays described by U.S. Pat. No. 5,882,944, issued Mar. 16, 1999, and U.S. Pat. No. 6,007,986, issued Dec. 28, 1999, to Sadxc3xa9e and pending application Ser. No. 09/200,012 now U.S. Pat. No. 6,270,979 the entire contents of all of which are hereby incorporated by reference. For example, the peptide CTAP was identified as a neutral antagonist in these assays, and was shown to elicit significantly less withdrawal than naloxone in drug-dependent mice (J. Pharm. Exper. Ther., 277: 484-190 (1996)).
Accordingly, the present invention relates to a method for the treatment of drug-dependency in a drug-dependent individual in need thereof comprising administering to the individual a therapeutically effect amount of a naloxone or naltrexone analog or a pharmaceutically acceptable salt thereof which is a neutral antagonist at the xcexc opioid receptor.
The naltrexone analogs suitable for use in the invention can be represented by Formula I and include the pharmaceutically acceptable salts thereof: 
wherein:
R1 is cycloalkyl(alkyl), for example, C3-C6 (cycloalkyl)alkyl, for example, C3-C6(cycloalkyl)methyl such as (cyclopropy)lmethyl or C5-C7(cycloalkenyl)alkyl;
R2 is H, OH or esters thereof, such as xe2x80x94OAc(O2C(alkyl)), for example O2(C1-C6 alkyl);
R3 is H, alkyl for example, C1-C6 alkyl, or (alkyl)Cxe2x95x90O for example, ((C1-C6)alkyl)-Cxe2x95x90O;
R4 and R5 are independently H, halogen (F, Cl, Br or I), alkyl, for example C1-C6 alkyl, alkoxy, such as C1-C4 alkoxy, nitro, amino, cyano, carboxyl or acyl which may be substituted for one or more hydrogens on the ring;
X is xe2x80x94OR6, xe2x80x94NR7R8R9, xe2x80x94NCOR10, xe2x80x94NO2, xe2x80x94SR11 
wherein,
R6 and R11 are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, for example C1-C6 acyl such as xe2x80x94C(O)xe2x80x94C1-C6 alkyl or aroyl,
R7, R8 and R10 are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl,
R9 and R12 can be present or absent and are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl
and phamaceutically acceptable salts thereof.
In a particular embodiment, the naltrexone analog is: 
and the pharmaceutically acceptable salts thereof.
The naloxone analog suitable for use in the method of the invention can be represented by Formula I: 
wherein:
R1 is alkenyl, for example a C3-C6 alkenyl, such as allyl
R2 is H, OH or esters thereof, such as xe2x80x94OAc(O2C(alkyl)), for example O2(C1-C6 alkyl);
R3 is H, alkyl for example, C1-C6 alkyl, or (alkyl)Cxe2x95x90O for example, ((C1-C6)alkyl)-Cxe2x95x90O;
R4 and R5 are independently H, halogen (F, Cl, Br or I), alkyl, for example C1-C6 alkyl, alkoxy, such as C1-C4 alkoxy, nitro, amino, cyano, carboxyl or acyl which may be substituted for one or more hydrogens on the ring;
X is xe2x80x94OR6, xe2x80x94NR7R8R9, xe2x80x94NCOR10, xe2x80x94NO2, xe2x80x94SR11;
wherein,
R6 and R11 are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, for example C1-C6 acyl such as xe2x80x94C(O)xe2x80x94C1-C6 alkyl or aroyl,
R7, R8 and R10 are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl,
R9 and R12 can be absent or present and are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl
and phamaceutically acceptable salts thereof.
In a particular embodiment, the naloxone analog is 
and pharmaceutically acceptable salts thereof.
In one embodiment, the drug-dependent individual is in long-term therapy to prevent relapse to drug use. In another embodiment, the drug-dependent individual is undergoing active withdrawal treatment. In yet another embodiment, the drug-dependent individual is undergoing acute treatment for a drug overdose. In a further embodiment, the drug-dependent individual is an infant born to a drug-addicted mother. In another embodiment, the individual is being administered opiate drugs for the treatment of pain as part of an anesthetic regimen.
The invention further relates to a method for the treatment of drug-dependency in a drug-dependent individual in need thereof comprising administering to the individual a therapeutically effective amount of a sustained release composition comprising a biocompatible polymer and an effective amount of a naloxone or naltrexone analog or the pharmaceutically acceptable salts thereof which is neutral antagonist at the xcexc opioid receptor. Use of a sustained release composition, as described herein, can be particularly desirable when the drug-dependent individual is under long-term therapy to prevent relapse to the drug of abuse.
The invention also relates to a kit, useful for treating drug dependency in a drug-dependent individual comprising a therapeutically effective dose of a naloxone or naltrexone analog, which is a neutral antagonist at the xcexc opioid receptor, and instructional materials associated with the dose. The kit is useful in the treatment of all drug dependent individuals such as those in long-term therapy to prevent relapse, individuals undergoing drug overdose treatment, individuals undergoing active withdrawal treatment and infants born to drug addicted mothers.
Therefore, agents which can be used in the treatment of drug dependency and in pain management but which have reduced aversive properties and can result in reduced withdrawal symptoms are provided by the present invention. Further, the agents described herein can be useful in a pain management regimen to modify the anesthesia/analgesia of an opioid drug or its undesirable side effects. In addition, the naltrexone and naloxone analogs described herein can be suitable for use in the treatment of eating disorders.